Isonipecotic acid compounds

ABSTRACT

ISONIPECOTIC ACID COMPOUNDS OF THE FORMULA:   (4-(R-OOC-)PIPERIDIN-1-YL)-CH&lt;(-(X,Y-1,2-PHENYLENE)-A-   (1,2-PHENYLENE)-)   WHEREIN A IS -CH2-CH2-, -CH=CH-, -CH2-SOR -CH2-OX AND Y ARE HYDROGEN, HALOGEN OR LOWER ALKOXY, AND R IS HYDROGEN OR LOWER ALKYL. THESE COMPOUNDS POSESS GASTRIC ANTISECRETORY AND ANTIULCER PROPERTIES.

United States Patent 3,763,169 ISONIPECOTIC ACID COMPOUNDS Charles Malen, Fresnes, and Xavier Pascaud, Paris, France, assignors to Science Union et Cie., Suresnes, France No Drawing. Filed Nov. 22, 1971, Ser. No. 203,101 Claims priority, application Great Britain, Dec. 2, 1970, 57,260/70 Int. Cl. C07d 67/00 US. Cl. 260-29357 4 Claims ABSTRACT OF THE DISCLOSURE Isonipecotic acid compounds of the formula:

X and Y are hydrogen, halogen or lower allt'oxy, and R is hydrogen or lower alkyl.

These compounds possess gastric antisecretory and antiulcer properties.

The present invention provides isonipecotic acid compounds of the general Formula I:

O O R I wherein:

In the meaning of X and Y, illustrative halogen atoms are chlorine, fluorine, and bromine, and illustrative alkoxy radicals are methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and the pentyloxy.

In the meaning of R, illustrative alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the pentyls.

3,763,169 Patented Oct. 2, 1973 The compounds of the general Formula I are new and are prepared according to a process which comprise condensing a halo compound of the general Formula II A X g/ m CH IIal II wherein A, X and Y have the meanings given above and Hal represents a chlorine or bromine atom, with an alkyl isonipecotate of the general Formula III:

wherein R represents a lower alkyl radical containing from 1 to 5 carbon atoms inclusive, in order to obtain a compound of the general Formula I wherein R represents a lower alkyl radical, then hydrolysing this resulting ester, advantageously in an aqueous-alcoholic medium, in order to obtain the corresponding compound of the general Formula I wherein R represents a hydrogen atom.

The condensation of the Compounds II and III is preferably carried out in a suitable organic solvent, for example nitromethane, acetonitrile or dimethylformamide.

The compounds of the general Formula I wherein R represents a hydrogen atom yield addition salts with inorganic bases such as bases of alkali or alkaline earth metals, for example, sodium, potassium or calcium hydroxide, carbonate or bicarbonate and with organic bases.

The compounds of the general Formula I wherein X and Y do not both represent a hydrogen atom and/or wherein A is an asymetric bridge may exist in the form of optical isomers and, although in this specification reference is made to the single Formula I, it is to be understood that, where they exist, all the optical isomers are included within the scope of the present invention.

The compounds of the general Formula I wherein R is a lower alkyl radical are crystalline white products, each having a well defined melting point. The compounds of the general Formula I wherein R is a hydrogen atom are generally solid products, the melting points of which are in fact decomposition points, so their determination is rather imprecise.

The following examples illustrate the invention, the melting points being determined in a Kofier block.

EXAMPLE 1 N-[2,3-dimethoxy-dibenzo (a,d) cycloheptadien-S-yl] isonipecotic acid CHz-CHa N -coon 48 g. (0.165 mole) of 2,3dimethoxy-S-chloro-dibenzo (a,d) cycloheptadiene in 450 ml. of nitromethane were poured, at once, in a solution of 52 g. (0.330 mole) of ethyl isonipecotate in 50 ml. of nitromethane. The reaction was slightly exothermic, and the mixture was heated at 60 C., on the waterbath, for one hour. The solvent was evaporated under vacuum, then the residue was taken up in chloroform and water. The organic phase was decanted olf, washed to neutrality, dried over sodium sulphate, and evaporated under vacuum.

III

O CH:

Using ethyl isonipecotate and, in place of ll-chloro dibenzo (b,e) thiepine,

ll-chloro-dibenzo (b,e) oxepine,

3-lower alkoxy-ll-chloro-dibenzo (b,e) oxepine, 2,3-di(lower alkoxy)-1l-cl1loro dibenzo (b,e) oxepine, 3-halo-1l-chloro-dibenzo (b,e) oxepine, and 2,3-dihalo-1l-chloro-dibenzo (b,e) oxepine,

there were respectively obtained N-[dibenzo (b,e) oxepin-ll-yl] isonipecotic acid,

N-[3-lower alkoxy-dibenzo (b,e) oxepin-ll-yl] isonipecotic acid,

N-[2,3-di-(lower alkoxy)-dibenzo (b,e) oxepin-ll-yl] isonipecotic acid,

N-[3-halo-dibenzo (b,e) oxepin-ll-yl] isonipecotic acid,

and

N-[2,3-halo-dibenzo (b,e) oxepin-ll-yl] isonipecotic acid.

The compounds of the general Formula I and physiologically tolerable salts thereof possess valuable pharmacological and therapeutic properties, especially gastric antisecretory and antiucler properties.

Their toxicity is weak and the LD in mice varies from 250 to 500 mg./kg. by intraperitoneal route and from 630 to 1000 mg./ kg. by intraperitoneal route and from The activity of the new compounds on the gastric secretion was demonstrated by the method of Shay H. et a1. (Gastroent. 5, 43, 1945). A 50% decrease of the volume and of the acidity of the secretion was observed with to 50 mg./kg. of the compounds administered by intraduodenal or by intraperitoneal route.

The compounds of the invention exhibit a very important protecting activity against the restraint ulcer and the ulcer provoked by phenylbutazone. The ED is between 44 and 150 mg./ kg. by oral or LP. administration.

The low toxicity and the above described pharmacological properties enable the use of the new compounds in therapy and especially in the treatment of gastroduodenal ulcers and gastric hypersecretion.

The present invention also provides pharmaceutical compositions comprising a compound of general Formula I or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier. The compositions may be administered by oral, rectal or parenteral route. The suitable pharmaceutical carriers are, for example, distilled water, starch, talc, glucose, lactose, or cocoa butter in order to obtain the suitable pharmaceutical forms such as, for example, tablets, dra-ges, capsules, suppositories or solutions.

The doses of active ingredient may vary from to 500 rng., preferably to 300 rng., 1 to 5 times in a day.

We claim:

1. A compound selected from the group consisting of (A) Isonipecotic acid compounds of the general formula:

COOR

wherein A is a radical selected from the group consisting of:

References Cited UNITED STATES PATENTS 3,252,984 5/ 1966 Cusic et al. 260-2934 HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R. 

